Substitute pyridinol-containing compositions and methods for the treatment of coccidiosis

ABSTRACT

A composition which comprises a pyridinol derivative of the formula   INTIMATELY DISPERSED IN AN INERT EDIBLE CARRIER, WHEREIN R1 and R2 may be the same or different and each represents a hydrogen atom; a lower alkyl group, an aralkyl group, an aliphatic, an aromatic or a heterocyclic acyl group; an alkoxycarbonyl group; an aralkoxycarbonyl group; an aryloxycarbonyl group; a Nsubstituted carbonyl group; a N-substituted thiocarbonyl group; a phosphono group; or a salt thereof. The composition is a preventive and curative anticoccidial agent for poultry and domestic animals. Particularly, it shows a significant activity against chronic coccidiosis caused by Eimeria acervulina. The composition is less toxic for animals, besides it has an advantage that it is also effective for coccidiosis caused by coccidia resistant to the known anticoccidial agents.

United States Patent [191 Morisawa et al.

[ SUBSTITUTE PYRIDINOL-CONTAINING COMPOSITIONS AND METHODS FOR THETREATMENT OF COCCIDIOSIS [75] Inventors: Yasuhiro Morisawa; MitsuruKataoka; Taiichiro Watanabe; Noritoshi Kit-ano; Toshiaki Matsuzawa, allof Tokyo, Japan [73] Assignee: Sankyo Company Limited, Tokyo,

Japan [22] Filed: Oct. 9, 1973 [21] Appl. No.: 404,641

[30] Foreign Application Priority Data Oct. 20, 1972 Japan 47-105090Apr. 11, 1973 Japan 48-41 1 ll [52] U.S. Cl. 424/263; 424/200; 424/266[51] Int. Cl A6lk 27/00 [58] Field of Search 424/263 [56] ReferencesCited OTHER PUBLICATIONS Rosen et al., Chem. Abst., Vol. 70, (1969),86l26a. Chem. Abst., Vol. 63, (1965), page l1489f. McCormick et al.,Vol. 55, (1961), page 24875i.

Primary Examiner-Frederick E. Waddell Attorney, Agent, or Firm-Flynn &Frishauf July 29, 1975 [57] ABSTRACT A composition which comprises apyridinol derivative of the formula intimately dispersed in an inertedible carrier, wherein R and R may be the same or different and eachrepresents a hydrogen atom; a lower alkyl group, an aralkyl group, analiphatic, an aromatic or a heterocyclic acyl group; an alkoxycarbonylgroup; an aralkoxycarbonyl group; an aryloxycarbonyl group; a N-substituted carbonyl group; a N-substituted thiocarbonyl group; aphosphono group; or a salt thereof.

The composition is a preventive and curative anticoccidial agent forpoultry and domestic animals. Particularly, it shows a significantactivity against chronic coccidiosis caused by Eimeria acervulina.

The composition is less toxic for animals, besides it has an advantagethat it is also effective for coccidiosis caused by coccidia resistantto the known anticoccidial agents.

24 Claims, No Drawings SUBSTITUTE PYRlDINOL-CONTAINING COMPOSITIONS ANDMETHODS FOR THE TREATMENT OF COCCIDIOSIS This invention relates to novelcompositions and methods for the treatment and prevention of the poultrydisease coccidiosis.

More particularly, it is concerned with novel compositions containing,as an active anticoccidial agent, certain pyridinol derivatives.

Coccidiosis is a common and widespread disease of poultry, especiallychickens and turkeys, and domestic animals such as rabbits, goats,sheep, and cattles, which disease is caused by a kind of protozoabelonging to class Sporozoa, order Coccidia, family Eimeriidae.

Coccidiosis of poultry and domestic animals is caused mainly by theprotozoa belonging to genus Eimeria, which disease is classified to anacute type and a chronic one.

The former is caused by such species as E. tenella and E. necarrix, andthe characteristic feature of the disease is a copious bloody dischargesfrom the ceca and small intestine of diseased poultry, which often diewithin a day or two.

The latter is caused by such species as E, acervulina, E. maxima, E.brunetti, E. praecox, E. hagani, E. mitis and E. mivati, and thecharacteristic feature of the disease is that the mortality of diseasedpoultry is rather few, whereas a poor weight gain, a reduced feedefficiency and a reduced efficiency of egg-production are commonlyobserved.

lnfant rabbits as well as cattles, sheep and goats sometime cause severelesions by parasite Eimeria within their levers and intestines.

Oocysts of coccidia are excreted from an infected animal with feces, andspores having infectivity are produced within 24 48 hours under suitableconditions, which spores enter into a noninfected animal orally.

Oocysts grow at first asexually within the cells of the caecum or smallintestine of the host animal, during which time the heaviest symptoms isobserved. Then, they grow sexually and are excreted with the feces ofthe host animal and they exhibit an awful communicability.

The elimination or control of coccidiosis is, therefore, of paramountimportance particularly in the poultry industry.

There have been proposed many preventive and curative methods forcoccidiosis. One of them is a development in chemotherapeutic agentssuch as sulfa drugs, arsenic compounds, nitrofuran derivatives,nitrophenide, Nicarbazine, Zelane, pyrimidine derivatives(anti-thiamines), quinoline derivatives, guanidine derivatives, variousantibiotics and so on.

But they have some defects; i.e. weak activity, narrow anti-protozoalspectrum, lack of security for animals or acquired resistance to thedrugs by protozoa, respectively. Therefore, treatment with thehither-toknown anticoccidial agent is not satisfactory.

it is an object of this invention to provide novel compositions whichare effective in treating and preventing coccidiosis.

Another objects will become apparent from the following detaileddescription of this invention.

ln accordance with this invention, it has now been found that thepyridinol derivatives having the formula wherein R and R may be the sameor different and each represents a hydrogen atom, a lower alkyl group;an aralkyl groups, an aliphatic, an aromatic or a heterocyclic acylgroup; an alkoxycarbonyl group; an aralkoxycarbonyl group; anaryloxycarbonyl group. a N- substituted carbamoyl group; a N-substitutedthiocarbamoyl group; a phosphono group; or a salt thereof possesssignificant anticoccidial activity, and may be used in the methods andcompositions of this invention.

The above compounds of formula (I) have a preventive and curativeanticoccidial activity against almost all species of genus Eimeriaespecially against E. acervulina to which no practically effectiveanticoccidial agents have been known.

In addition, some of the above compounds have a growth promotingactivity for poultry and domestic animals and their preventiveapplication to non-infected animals brings the promotion of weight gainand the improvement of feed efficiency.

With regard to the above formula (I), the lower alkyl group may bepreferably of l to 3 carbon atoms and exemplified by methyl, ethyl,n'propyl or isopropyl; the aralkyl group may be preferably benzyl groupwhich may have halogen atom(s) such as chlorine in the benzene ring; thealiphatic acyl group may be a straight or branched alkanoyl or alkenoylgroup of 2 to 18 carbon atoms in total, and the aliphatic acyl group mayhave substituents such as aryloxy group, and the aliphatic acyl groupmay be cycloalkanoyl group of 6 to 8 carbon atoms in total, andexemplified by acetyl, propionyl, butyryl, valeroyl, hexanoyl, octanoyl,palmitoyl, stearoyl, isobutyryl, isovaleroyl, pivaloyl, crotonoyl,phenoxyacetyl, 2-phenoxypropionyl or cyclohexanecarbonyl; the aromaticacyl group may be preferably a benzoyl or a naphthoyl group which mayhave 1 to 2 substituents such as lower alkyl-, alkoxy-, halogen-,nitro-, cyano-, carboxy-, or acetylaminoin the aromatic ring andexemplified by benzoyl, naphthoyl, toluoyl chlorobenzoyl, bromobenzoyl,methoxybenzoyl, nitrobenzoyl, cyanobenzoyl, carboxybenzoyl,acetylaminobenzoyl, 3,5dim' ethylbenzoyl, 2,3-dimethoxybenzoyl or3,4-dimethoxybenzoyl group; the heterocyclic acyl group is exemplifiedby 2-furoyl, Z-thenoyl, isonicotinoyl or nicotinoyl group; thealkoxycarbonyl group may have preferably 1 to 8 carbon atoms in thealkyl moiety and exemplified by methoxycarbonyl, nbutoxycarbonyl oroctoxycarbonyl group; the aralkoxycarbonyl group is exemplified bybenzyloxycarbonyl group; the aryloxycarbonyl group is exemplified byphenoxycarbonyl group; the carbamoyl group may have a substituent on thenitrogen atom such as a lower alkyl group of l to 2 carbon atoms, acycloalkyl group of 5 to 7 carbon atoms or a substituted orunsubstituted phenyl group and exemplified by ethylcarbamoyl,cyclohexanecarbamoyl, phenylcarbamoyl or chlorophenylcarbamoyl group;the thiocarbarnoyl group may have a substituent on the nitrogen atomsuch as a lower alkyl group of l to 2 carbon atoms, a cycloalkyl groupof 5 to 7 carbon atoms or a substituted or unsubstituted phenyl groupand exemplified by ethylthiocarbamoyl,

cyclohexylthiocarbamoyl, phenylthiocarbamoyl orchlorophenylthiocarbamoyl group.

In view of anticoccidial activity, preferable are the followingpyridinol derivatives:

A compound in which both R, and R in the formula (I) are hydrgoen atom;a compound in which R; is hydrogen atom and R is an alkanoyl group of 2to 8 carbon atoms, an alkenoyl group of 3 to 8 carbon atoms, acycloalkanoyl group of 6 to 8 carbon atoms, a furoyl group, a tenoylgroup or a benzoyl group unsubstituted or substituted with a methyl ormethoxy group; a compound in which R is hydrogen atom and R is analkanoyl group of 2 to 8 carbon atoms, an alkenoyl group of 3 to 8carbon atoms, a cycloalkanoyl group of 6 to 8 carbon atoms or aphosphono group; a compound in which both R, and R may be the same ordifferent, are alkanoyl group of 2 to 8 carbon atoms or alkenoyl groupof 3 to 8 carbon atoms.

More preferably are the following pyridinol derivat1ves:

A compound in which both R and R in the formula (l) are hydrogen atom; acompound in which R is a hydrogen atom and R is an alkanoyl group of 2to 8 carbon atoms; a compound in which R is a hydrogen atom and R is analkanoyl group of 2 to 8 carbon atoms or a phosphono group.

The acid adduct salts of the above formula (I) also possessanticoccidial activity,

There is no limitation to the acid so far as salts formed arepharmaceutically acceptable and nontoxic to animals.

Suitable salts of this invention are as follows:

acid adduct salts in which an acid is such inorganic acid ashydrochloric acid, sulfuric acid, nitric acid or phosphonic acid; suchorganic acid as acetic acid, propionic acid, lactic acid, oxalic acid,suceinic acid, maleic acid, tartaric acid, citric acid, benzoic acid,phthalic acid, terephthalic acid, naphthalene disulfonic acid.

Of the pyridinol derivatives of the above formula (I), representativeexamples thereof are listed below, but they are not intended to belimiting the scope of this invention.

l8 -aeetoxymcthyl-2-methyl-3-palmitoyloxypyridine -Continued CompoundNo. Chemical Name 19 S-acctoxymethyl-2-mcthyl-3stearoyloxypyridinc 2O5-mcthoxymcthyl-2-methyl-B-pyridinol 215-hcnzyloxymcthyLZ-mcthyl-3-pyridinol 225-(p-chlorobcnzyloxymethyll-2-methyl-3-pyridinol 233-benzyloxy-5-hydroxymethyl-Z-mcthylpyridinc 245-hydroXymcthyl-3-methoxy-Z-mcthylpyridinc 25B-acctoxy-S-hydroxymethyl-Z-mcthylpyridinc 26S-hydroxymethyl-Z-mcthyl-3-propionyloxypyridinc 273-butyryloxy-5-hydroxymcthyI-Z-mcthylpyridinc 285-hydroxymcthyl-Z-mcthyl-3-valcroyloxypyridinc 293-hcxanoyloxy-S-hydroxymethyl-Z-mcthylpyridinc 30S-hydroxymcthyl-2-mcthyl-3-octonoyloxypy ridinc 3 l5-hydroxymethyl-3-lauroyloxy-Z-methylpyridine 325-hydroxymcthyl-2-mcthyl-3-palmitoyloxypyridinc 335-hydroxymcthyl-Z-methyl-3-stearoyloxypyridinc 34S-hydroxymcthyl-3-isobutyryloxy-Z-mcthylpyridine 353-crotonoyloxy-5-hydroxymethyl-2-mcthylpyridinc 363-cyclohexanecarbonyloxy-S-hydroxymethyl-Z- methylpyridine 375-hydroxymcthyl-2-methyl-3-phenoxyacetoxypyridine 38S-hydroxymcthyl-2-methyl-3-(a-phenoxypropiony'loxy )pyridine 393-bcnzoyloxy-5 hydroxymethyl-2-methylpyridinc 40 5-hydroxymethyl3-(p-mcthoxybcnzoyloxy J-2- methylpyridine 4l 5-hydroxymethyl-3-(o-mcthoxybenzoyloxy )-2- methylpyridine 425-hydroxymethyl-2-mcthyl-3-(p-toluoyloxy pyridine 435-hydroxymethyl-2-mcthyl-3-(m'toluoyloxyy yridine 44S-hydroxymethyl-Z-methyl-3-(o-toluoyloxy)- pyridine 45 3(3,5-dimethylbenzoyloxy )-5 hydroxymethyl-2- mcthylpyridine 46 3-(3,4-dimethoxybenzoyloxy)-5-hydroxymcthyl-2- mcthylpyridinc 47 3-( 2,3dimethoxybenzoyloxy)-5-hydroxymcthyl-2- mcthylpyridine 483-(p-chlorobenzoyloxy)-5-hydroxymethyl-Z-methylpyridine 493-(o-chlorobcnzoyloxy)-S-hydroxymethyl-Z-mcthylpyridine 505-hydroxymcthyl-2-methyl-3-(p-nitrobenzoyloxy)- pyridine 513-(p-cyanobcnzoyloxy )-5-hydroxymcthyl-Z-methylyridine 52 3-(2-furoyloxy )-5-hydroxymethyl-Z-methylpyridine 5 35-hydroxymcthyl-2-mcthyl-3-( 2thenoyloxy )pyridine 54S-hydroxymethyl-2methyl-3-nieotinoyloxypyridine 55 3-(p-acetylaminobenzoyloxy)-5-hydroxymethyl-2- mcthylpyridine 565-hydroxymcthyl-2-methyl-3(a-naphthoyloxy) pyridine 575-acctoxymethyl-2mcthyl3-pyridinol 582-methyl-5-propionyloxymethyl-3-pyridinol 595-butyryloxymethyl-2-methyl-3-pyridinol 60 2-methyl-5valeroyloxymethyl-3-pyridinol 6l5-hexanoyloxymethyl-2-methyl-3-pyridinol 62 2-methyl5-octanoyloxymethyl-3-pyridinol 635-lauroyloxymethyl-Z-methyl-3-pyridinol 642-methyl3-palmitoyloxymethyl-3-pyridino] 652-methyl-5-stcaroyloxymethyl-3-pyridinol 665-isobutyryloxymethyl-2-methyl-3-pyridinol 67 S-crotonoyloxymcthyl-Z lmethyl-3-pyridinol 68 5-cyclohexanccarbonyloxymethyl-2-methyl-3-pyridinol 69 2-mcthyl-5-phenoxyacctoxymethyl3-pyridinol 705-benzoyloxymethyl-2-methyl--3-pyridinol 71 5-(p-mcthoxybcnzoyloxymethyl )-2-methyl-3- pyridinol 722-methyl-5-(p-toluoyloxymethyl )-3-pyridinol 73 5p-chlorobenzoyloxymethyl )-2methyl-3- pyridinol 745-(o-chlorobenzoyloxymethyl)-2-methyl3- pyridinol 755-(p-bromobcnzoyloxymethyl)-2-methyl-3-pyridinol 76 2-methyl-5-(p-nitrobcnzoyloxymcthyl )-3-pyridinol 775-(p-cyanobenzoyloxymethyl)-2-methyl-3-pyridinol 78 5-(2-furoyloxymcthyl )-2-methyl-3-pyridinol 79 2-mcthyl-5-(N-phcnylcarhamoyloxymethyl )-3- pyridinol 80 5-(N-p-chlorophenylcarbamoyloxymethyl )-2-mcthyl- 3-pyridinol 8i 5-(N-cyelohcxylcarbamoyloxymethyl )-2-mcthyl-3- pyridinol 82 2-mcthyl-5-( Nphenylthiocarbamoyloxymethyl )-3- -Continued -Continued Com- Compoundpoun No. Chemical Name 5 No. Chemical Name pyridinol 7 t 835-(N-p-chlorophcnylthiocarbumoyloxymcthyl)-2 5 332 1 i ggggtwggggg 5phenylthm rfflhyl'3'pyndlml 1273-acctoxv-5-mcthoxycarbonyloxymethyl-2-methyl- 184N-cyclohcxanclhiocarbumoyloxymcthyl )-2- pyridine methyl-3-pyridinol q nu l b' 1 th 1- B5 2-methyl-S-nicotinoyloxymcthyl-Ii-py idinol l PhcnyXyme y 2'mchyl'j'phosphonoxymcthyl'3'pynd'nol 1293-acetoxy-5-ethylthiocarbamoyloxymethyl-Z- 875-methoxycarbonyloxymcthyl-2-mcthyl-3-pyr dinol mam/pyridine 88-butoxycurbonyloxymcthyl-2-mcthyl-3-pyridmol 130 3mcthoxycarbonyloxyavmethyLswalemyloxyv B9J-benzyloxycarbonyloxymcthyl-Z-mcthyl-3- mclhylpyridine pyndmol l3]3-methoxycarbonyloxy-2-methyl-5-phenylcarbamoyl- )02-mcthyl-5-phenoxycurbonyloxymethyl-B-pyrrd1nol oxymethvlpyridine Q1'uccwxy's'he"20y]Oxymcthyl'z'mcthylm'ndno I 5 1325-acctoxymethyl-3-ethylcarbamoyloxy-Z-meihyl- 923-acetoxy-5-(p-chlorobcnzoyloxymelhyl)-2- pyridine mcthylpyridinc 933-acetoxy-5-(p-methoxybcnzoyloxymethyl)-2- L @Rimgfiggggiggfig 2 methylphenyl mcthylpyridine t 94 3-acetoxy-5(lfuroyloxymethyl)-Z-methylpyridinc 134 5 s 'sg methyl 3 '953-acctoxy-5-cyclohexanccarbonyloxymethyl-Z- py mcthylpyridine 965-benzoyloxymcthyl-2-mcthyl-3-propionyloxypyridine I 975WeIOhcxanccarbonyloxymethyl2 methyl 3 The most preferable group of thepyridinol derrva yulcroyloxypyridine tives of the above formula (l) mayinclude the follow- 98 5-acctoxymethyl-3-cyclohexanecarbonyloxy-Z- iCompounds:

methylpyridinc v 99 S-ucetoxymethyl-3-crotonoyloxy-Z-methylpyridine 5 hd h 2 h 3 idi I00 3-ucctoxy-5-crotonoyloxymethyl-2methylpyridine 5 l h l2 h l 3 .d. l lUl 3-crotonoyloxy-5-crotonoyloxymethyl-2-methyl-'dcetoxymet y: y Py pyridine 2-methyl-5-propionyloxymethyl-3-pyridinolE02 5 -crotyorioylogymethyl-3-cyclohexane-curbonyloxyy y y y y py y..-mct ypyri me l03 3-crotonoyloxy-5-cyclohexanecarbonyloxymethyl-5-valeroyloxymethyl-3-pyridinol Z-methylpyridinc I043-cyclohexanecurbonyloxy-S-cyclohexanecarbonyl 3O 5 hexanoyloxymethyl 2mfithyl 3 pyr ld mOl 0xymethyl-Z-mcthylpyridineZ-methyl-S-octanoyloxymethyl-3-pyridinol y fly:-g-{ 'g ygiy pypgZ-methyl-S-phosphonoxymethyl-3-pyridinol b-acctox'mc -mc oxy cnzoyoxymcthylpgridincy p 3-acetoxy-5-hydroxymethyI-Z-methylpyridme z 'i lg gfigg From the industrial point of view, the most preferable propiony oxy W83-(p-mcthoirybcnzoyloxy)-2methyl-5-vuleroyl xycompound 185-hydroxymethyl-2-methyl-3-pyndmol [ncthylpyrdmc The Compound No." asgiven in the foregoing will I09-1-hexanoyloxymethyl-Z-mcthyl-3-(p-toluoyloxy)- b h ft f d t pyridine eereina er re erre o. l 5'ulcgwxymcthyl'34pchlombcnzoymxyl'zmcthl'L Amongthe above illustrated compounds, compounds Tl inc 1 gi h yarbonyloxy-S-mcthoxycarbonyloxymethyl- NO. I and NO. 2 are described inThe Journal Of the 7 gi y py 5 b b 1 th 1 American Chemical Society vol.69, 2574 pp., (1947), [1. utoxycar ony oxyutoxycur onyoxyme y- Izmmhylpyridinc but other compounds have not been known yet. 3'L%i Theabove new compounds are readily prepared ac- -mct y Tl me I143-bcn2ylizycarbonyloxy-S-bcnzyloxycurbonyloxy- Cordlng to the Processdescribed heremaftermethyl-Z-methylpyridine I152-mcthyl-3-phenoxycarbonyloxy-5-phenoxycarbonyl- Process for thepreparatlon of 3 e ster de oxymcthylpyridine rivatives of5-hydroxymethyl-2-methyl-3-pyridmol no cn on cn on a H CH N c 3 (II)(III) I16 af y yl i y y y lwherein R is an aliphatic, an aromatic or aheterocypyri inc l17 2-mcthyl-3-nicotinoyloxy-Smicotinoyloxymcthyl- Cheacyl P- Pyridine A Method with an acid anhydride and water ?5.5-Hydroxymethyl-Z-methyl-B-pyridinol (II) or the pyri inc 1 l93-bcnzoyloxy-5-henzoyloxymethyl-2-methylpyridine 6O salt thereof 15dissolved in water. In case the salt is used, 130 f l the solution isneutralized with an equimolar alkali or methyl)-2-mcthylpyridinc l2|3-(2-tenoyl0xyl)-5-(Z-tcnoyloxymcthyl)-2-mcthyla tertiary amine.

The reaction is erformed b the addition of a satu- 122 3-cthylcarburnoyIoxy-S-cthylcarhamoyloxymcthyld r h y b l, h d d f Z-mcthylpyndmgrated or unsaturate a 1p atic car oxy to an y n e o 133 l' -l l m' y y-'p y 2 to 8 carbon atoms to the solution to form the comoxymcthylpyndincd f f l "1 I24 3-cyclohcxunccurbamoyloxy-S-uyclohcxanc poun 5 O acurbamoyloxymcthyl-2-mcthylpyridine A Method with an acid halide, anamine and an orl"53-cthylthiocarbumoyloxy-S-cthylthiocurbumoyloxymelhyl-Z-mcthylpyridincganic solvent CH N alkali or a tertiary amine. In case a salt is used,the addition of 2 molar alkali or tertiary amine is necessary forneutralization.

The reaction is performed by the addition of an equimolar aliphatic,aromatic or heterocyclic carboxylic halide to the solution to form thecompounds of formula (Ill).

According to the above process (A), compounds Nos. 25 to 56 areobtained. The examples of the process (A) will be described asreferential examples 1 to 4 below. (B) Process for the preparation of-mono- B Method with an acid anhydride, an amine and an organic solvent5-Hydroxymethyl-2-methyl-3-pyridinol or. the salt thereof is reactedunder heating with an equimolar aliphatic. aromatic or heterocycliccarboxylic anhydride in an aprotic solvent in the presence of pyridineor a tertiary amine to form the compounds of formula (V). The method issuitable for obtaining S-mono-ester derivatives in one step in goodyield. B Method by the selective hydrolysis of 3,5-diesters of5-hydroxymethyl-2-methyl-3-pyridinol H CH OR hydrolysis CH N wherein Rand R may be the same or different, are aliphatic, aromatic orheterocyclic acyl group.

The 3,5-Diesters of 5-hydroxymethyl-2-methyl-3- pyridinol or the saltsthereof are selectively hydrolyzed in the presence of an acid to formthe compounds of formula (V)v According to the above process (B),compounds Nos. 57 to 78, No. 85 and No. 134 are obtained. The examplesof the process (B) will be described as referential examples 5 to 8below.

ester derivatives of 5-hydroxymethyl-2-methyl-3- C. Process for thepreparation of 2 -methyl-5- pyridinol phosphonoxymethyl-B-pyridinol 11ca 05 HO ca x 2 HBr, POCl or SOC1 2 -a k 3 N cH v) R 0A 3 2 3 g A R OH 0CH OR CH \N l CHZOH ao\ /cn -0-1l oa k polyphosphorlc acld OH CH CH N ortetrachloropyr 3 wherein R has the same meaning as described in para-.

graph (A); X is a halogen atom. 8,. Method with5-halomethyl-2-methyl-3-pyridinol and a silver salt or an organic acid.

5Hydroxymethyl-2-methyl-3-pyridinol (II) or the salt thereof is heatedwith hydrobromic acid, phosphorus oxychloride or thionyl chloride toform 5- halomethyl2-methyl-3-pyridinol (IV). The compound (IV) thusobtained is reacted with a silver salt of an organic acid in thecorresponding organic acid to form the compounds of formula (V).

phosphoric acid our cn o uaR (VIII) T CH OJNI-I-R wherein R is analkyL'a cycloalkylor an aryl group. 9 in Jan aproticsolventin thepresence ofpyridine or a 5Hydroxymethyl-2-methyl 3'pyridin0l or f the?salt 1 I (at) a thereof lS dissolved 'orsuspended m an aprotic solvent.

The reaction is performed by the addition of an equimolar isocyanate orisothiocyanate to the solution to form the compounds of forn'iula(Vlll')c t-(IX)? According to the above processi'lDl',"Compounds' Nos. 79 toare obtained. 1.

The example ofthe process-(D) wilLbe desc-r ibed as the referentialexample 11 below. 7 i

E. Process for the preparation of 5. -.carb

wherein R is an alkyl, an aralkyl or an aryl group.

5-Hydroxymethyl-2-methyl-3-pyridinol (H) is reacted with achlorocarbonate having the formula 0 ll (ICORH tertiary amine to formthe compounds of formula (X).

. hy ro y wherein R has the same meaning as described in paragiaph"(E,); R is an aliphatic acyl group, alkoxycarbonyl group,aralkoxycarbonyl group or an aryloxycar bonyl group.

selective hydrolysis of the compounds ofthe formula (X1) in a dilutedacid Accordinto the above process (E compounds No,

" 87 to 90 are obtained.

OCOR

(in i The examples of process (E) will be described in referentialexamples l2 and 13 below.

F. Process for the preparation of 3,5-disubstituted 5hydroxymethyl-3-methyl-3-pyridin0ls (diester, dicar- 5 bamate ordicarbonate derivatives having the same substituents on 3- andS-positions) Compounds of the formula (X) are obtained by the,

R50\ CH20R3 ca 3 (XII) H0 c3 03 RSHNCO ca -ocnna CH3/ (XIII) (II) fifiocon CH2- 'OCOR6 3 (XIV) wherein R R and R have the same meaning asdewherein R is an alkyl or aralkyl group.

scribed above, respectively. 5-Hydroxymethyl-2-methyl-3-pyridinol (ll)or the 3,5-Diester, dicarbamate and dicarbonate derivatives salt thereofis dissolved in dimethylformamide. To the of5-hydroxymethyl-2-methyl-3-pyridinol having the solution is added ametal halide or a metal alcoholate same substituents on 3- and5-positions are obtained and the solution is stirred. according to theaforementioned process (A), (B), (C) The reaction is performed by theaddition of an alkyl or (D) by using 2 molar or more correspondingreachalide or an aralkyl halide to form the compounds of tions. formula(XV).

According to the above process (F), compounds No. H Method for obtainingS-mono ether derivaitves EMU CH X B H CH2OR CH N CH 101, No. 104, Nos.111 to 117 and Nos. 119 to 126 are wherein X and R have the same meaningas defined obtained. above, respectively.

The examples of the process (F) will be described in 5 2 3- or the saltreferential examples 14 to belowthereof is heated with the alcohol offormula R OH to 6 Process for the Preparation of 3, 5-disubstimted formthe corresponding compounds of formula (XVI).5'hydmxymethyl'z'methyl'3'pyridinols (diesters' According to the aboveprocess (H), compounds of dicarbamates or dicarbonates having thedifferent sub- NOS. 20 to 24 are obtained. stituents each other on 3-and 5-positions) Such compounds are obtained by optional combination ofthe processes for the preparation of the 3- or S- substitutedderivatives described in (A), (B), (C) or (m REFERENTIAL EXAMPLE 1According to the above process (G), compounds Nos. 91 to 100, No. 102,No.103, Nos. 105 to l 10, No.

The examples of process (H) will be described in the referentialexamples l8 and l9.

11s and Nos. 127 to 133 are obtained. yy y y y py y The example ofprocess (G) will be described in the Chloride (hydrochloride of 25)referential example To a solution of 3.5 g. S-hydroxyinethyl-Z-methyl-H. Process for the preparation of 3- or 5-mono ether 3 idin l in 15 ml,of water was added 1.7 g. of soderivatives of5-hydroxymethyl-2-methyl-3-pyridinol dium bicarbonate to neutralize thesolution. To the so- H Method for obtaining 3-mono ether derivativeslution was added 2.5 g. of acetic anhydride under stirl-lon cn on R\ caon CH3 01 \N (In I (xv) ring at room temperature and the stirring wascontinued for 20 minutes and the product was taken up in ethyl acetate.I

The extract was dried over anhydrous sodium sulfate and concentratedinto dryness to give an oil, which was again dissolved in 15 ml. ofethyl acetate and the desired product as colorless crystals wasseparated out by the addition of 5 ml. of 15% ethanolic hydrochloricacid to the solution. r t

Yield 3.4 g. m.p. 134- 135C Analysis for C HC1NO Calculated: C, 49.61;H, 5.56; N, 6.48

Found: C, 49.82; H, 5.62; N, 6.58

IR spectrum (Nujol Mull, cm").

NMR spectrum (7, D

7.28 (3H, s, C2-CH3) 5.09 (2H, s,'C -CH OH) 1.58 (1H, d, J=2.0 c,-H 1.39(11-1, d, .l=2.0 c.,-H)

REFERENTIAL EXAMPL :7

3-Hexanoyloxy-5-hydroxymethyl-2-methylpyridine hydrochloride(hydrochloride of No. 29) a To a solution of 0.9 g. of5-hydroxymethyl-2- methyl3-pyridino1 hydrochloride in 10 ml. of pyridinewas added 0.67 g. of caproyl chloride in 5 ml. of pyridine dropwiseunder cooling and stirring.

The resulting mixture was stirred overnight at a room temperature,poured into ice water and extracted with ethyl acetate.

The extract was washed with water, dried over anhydrous sodium sulfateand the solvent was distilled off to give an oily residue.

The residue was purified by column chromatography (25 g. of silica gel)and 0.9 g. of an oily substance eluted with benzene-ethyl acetate (7:3followed by 5:5) was dissolved in ethyl acetate. The desired product ascolorless crystals wasseparated out by the addition of ethanolichydrochloric acid to the solution.

m.p. 127- 129C Analysis for C H ClNO Calculated: C, 57.0; H, 7.31; N,5.12; C1, 12.97

Found: C, 57.28; H, 7.40; N, 5.33;'Cl, 12.99

IR spectrum (Nujol Mull, cm)

NMR spectrum (1', D 0) 7.33 (3H, s, C -CH 11 7.17 (2H. t. J=7.5,OCCHZSCH2)I|CHJ) s. 10 (211, C -CH OH.)

REFERENTIAL EXAMPLE 3 3-Hexanoy1oxy-5-hydroxymethy1-2-methylpyridinehydrochloride (hydrochloride of No. 29)

To a solution of 0.9 g. of 5-hydroxymethy1-2- methyl3-pyridinolhydrochloride and 1.0 g. of triethylamine in 10 ml. of water was added0.67 g. of n-caproyl chloride dropwise under stirring. After thestirring was continued for 30 minutes, the resulting mixture wasextracted with ethyl acetate.

The extract was washed successively with 5% sodium bicarbonate and waterand dried over anhydrous sodium sulfate. After the extract wasconcentrated. the desired product as colorless crystals was separatedout by the addition of 15 percent ethanolic hydrochloric acid. Yield 0.7g., melting point 127 129C.

The IR spectrum of the above compound coincided with that of thestandard.

REFERENTIAL EXAMPLE 4 5 -Hydroxymethyl-3-(p-methoxybenzoyloxy )-2-methylpyridine (No. 40)

To a solution of 0.9 g. of 5-hydroxymethyl-2- methyl3-pyridinolhydrochloride in 5 ml. of anhydrous pyridine was added 0.86 g. ofp-anisoyl chloride dropwise under cooling. After standingovernight theresulting mixture was poured into ice water and extracted withchloroform.

The extract was washed with water and dried over anhydrous sodium,sulfate. 1.4 g. of the desired product as colorless crystals wasobtained by removing the solvent. an d 'recrystallization from ethylacetate and nhexane.

m.p., 103- 104C Analysis for C,,=,H, NO

Calculated: C, 65.92; H, 5.53; N, 5.13

Found: C, 65.82; H, 5.50; N, 5.01

IR spectrum'(Nujol Mull, cm)

NMR spectrum (1', CDCI 7.56 (3H, s, C -CH 6.34('1H, broad W1/2=10, OH)

6.11 (3H, s, OCH

5.30 (2H, s, C -CH OH) 3.oo (2H, d, J=9 MeO 2.43 (1H, d, .1 =1.5,C -1-l)1.84 (2H, d, J=0 MeO 1.70 (1H, d, J=l.5, C -H) Following thesubstantially same procedure as shown in the referential examples 1 to4, those pyridine derivatives as recited below were prepared:5-Hydroxymethyl-2-methyl-3-octanoyloxypyridine (N0. 30)

Colorless oil, 1

R, value of thin-layer chromatography: 0.63

-Continued 11 8.2 8.9 (4H. m, OCCH- Cl-l CH CH 11 t. OCCH-CH CH Cl-h)4.91 (2H. s, C CH OCR) REFERENTIAL EXAMPLE 75-Benzoyloxymethyl-2-methyl-3-pyridinol (No. 70)

0.5 g. of 3-acetoxy-5-benzoyloxymethyl-2-methyl pyridine was added to 25m1. of 2N hydrochloric acid and stirred for one hour at 80C, duringwhich time the mixture was one dissolved, then a crystal was separatedOut.

The reaction mixture was neutralized with potassium bicarbonate andfiltered off.

The crystal separated was recrystallized from ethanol to give 0.2 g. ofthe desired product as colorless crystals.

m.p. 221 223C Analysis for C H NO Calculated: C, 69.12; H, 5.39; N, 5.76

Found: C, 69.18; H, 5.30; N, 5.66

IR spectrum (Nujol Mull, cm") NMR spectrum ('r, CF COOH) 7.18 (3H, s, C-CH 2.15 2.50 (3H, m, Aromatic H) 1.90 (1H,d,.1=2.0, C -H) 1.76 (1H, d,J=2.0, C -H) 1.60 1.95 (2H, m, Aromatic H) REFERENTIAL EXAMPLE 85-(Z-Furoyloxymethyl)-2-methyl-3-pyridinol (No. 78)

0.98 g. of 3-(2-furoyloxy)-5-(2-furoyloxymethyl)- 2methylpyridine washeated at 75C for one hour in 20 ml. of 2N hydrochloric acid.

The solvent was distilled off under reduced pressure, and the residuewas diluted with 20 ml. of water and neutralized with sodium bicarbonateand extracted with ethyl acetate.

The extract was washed successively with an aqueous solution of sodiumbicarbonate and water and after dried over anhydrous sodium sulfate thesolvent was distilled off.

The resulting residue was purified by silica gel chromatography and 0.46g. of the desired product as colorless crystals was obtained from theeluate with ethyl acetate.

m.p. 192C Analysis for C H NO,

Calculated: C, 61.80; H, 4.75; N, 6.01

Found: C, 61.65; H, 4.58; N, 5.96

IR spectrum (Nujol Mull, cm)

NMR spectrum (1-(CD SO) 7.64 (3H, s, C -CH 4.70 (2H, s, C -CH OCOR) 3.27(1H, q, J=3.5, 1.0 Furan C -H) 2.75 (1H, d, J=2.0, C,-H)

2.62 (1H, q, .l=3.5, 1.0, Furan C -H) 1.85 2.02 (2H, broad, C -H of thepyridinol and C -H of the furan ring are overlapped) Following thesubstantially same procedure as shown in referential examples 5 8, thosepyridine derivatives as recited below were prepared.2-Methyl-5-propionyloxymethyl-3 -pyridin0l (No. 58)

Colorless crystal, m.p. 149 150C Analysis for C H NO Calculated: C,61.52; H, 6.71; N, 7.18

Found: C, 61.59; H, 6.76; N, 7.362-Methyl-5-octanoyloxymethyl-3-pyridinol (No. 62)

Colorless crystal, m.p. 107 108C Analysis for C H NO Calculated: C,67.89; H, 8.74; N, 5.28

Found: C, 67.87; H, 8.64; N, 5.065-lsobutyryloxymethyl-2-methyl-3-pyridinol (No. 66)

Colorless crystal, m.p. 143 145C Analysis for C H NO Calculated: C,63.14; H, 7.23; N, 6.69

Found: C, 63.49; H, 7.00; N, 6.775-Crotonoyloxymethy1-2-methy1-3-pyridino1 (No. 67)

Colorless crystal, m.p. 153C Analysis for C H NO Calculated: C, 63.75;H, 6.33; N, 6.77

Found: C, 63.62; H, 6.35; N, 6.935-(p-Methoxybenzoyloxymethyl)-2-methyl-3-pyridinol hydrochloride(hydrochloride of No. 71)

Colorless crystal, m.p. 221 223C (dec) Analysis for C H ClNO Calculated:C, 58.70; H, 4.24; N, 4.56; Cl, 11.56

Found: C, 58.59; H, 4.60; N, 4.5; Cl, 11.905-Cyclohexanecarbonyloxymethyl-2-methyl-3- pyridinol (No. 68)

Colorless crystal, m.p. 173 175C Analysis for C H NO Calculated: C,67.44; H, 7.68; N, 5.62

Found: C, 67.20; H. 7.66; N, 5.762-Methy1-5-(p-nitrobenzoyloxymethyl)-3-pyridinol hydrochloride(hydrochloride of No. 76)

Colorless crystal, m.p. 210C Analysis for C H CIN O Calculated: C,51.70; H, 4.02; N, 8.63; Cl, 10.94

Found: C, 51.52; H, 3.78; N, 8.75; Cl, 10.96

Referential Example 9 2-Methyl-5-phosphonoxymethyl-3-pyridinol (No. 86)

2.6 g of 5-hydroxymethyl-2-methyl-3-pyridinol was added to 15 g. ofpolyphosphoric acid and the mixture was heated at 90C for 5 hours. Afterthe completion of the reaction, the resulting mixture was diluted with30 m1. of water and heated for one hour at 100C to hydrolyze theresulting polyester to the monoester.

After cooling, the mixture was neutralized with barium carbonate and theprecipitate formed was filtered off.

The filtrate was concentrated under reduced pressure and adjusted to pH2.5 3.0.

The crystal separated out by cooling was filtered and recrystallizedfrom water-acetone and dried at 70- 80C to give 0.42 g. of the desiredproduct as colorless crystals.

Analysis for C H NO P 19 Calculated: C, 38.41; H, 4.60; N, 6.40; P,14.02 Found: C, 38.44; H, 4.55; N, 6.16; P. 13.82 IR spectrum (NujolMull, cm) V 2500,U p NMR spectrum (7, D 0, DCl) 7.32 (3H, s, C -CH 4.85(2H, s, C -CH OPO H 2.02 (1H, d, .l=2.0 C =Hl 1.72 (1H,d,.1=2.0 C,;-H)

REFERENTIAL EXAMPLE l0 2-Methyl-5-phosphonoxymethyl-3-pyridinol (No. 86)

1.3 g. of 5-hydroxymethyl -2-methyl-3-pyridin0l was added to 5.0 g. oftetrachloropyrophosphoric acid cooled to -C under stirring. After theadditional stirring for 2 hours, the mixture was allowed to standovernight at 0C, then diluted with 100 ml. of 1N hydrochloric acid.Thereafter, following the substantially same procedure as shown inreferential example 9, 0.2 g. of the desired product was obtained.

REFERENTIAL EXAMPLE 1 l 2-Methyl-5-(N-phenylcarbamoyloxymethyl-3-pyridinol (No. 79)

To a solution of 0.9 g. of 5-hydroxymethyl-2-methyl- 3-pyridinolhydrochloride in 5 ml. of pyridine was added 0.3 g. of phenylisocyanateand the mixture was stirred at room temperature for hours. After thepyridine was distilled off under reduced pressure, the resulting residuewas poured into 15 ml. of water, neutralized with sodium bicarbonate andextracted with ethyl acetate.

The extract was dried over anhydrous sodium sulfate and the solvent wasdistilled off. The resulting crystal was recrystallized from ethylacetate and ether to give 0.55 g. of the desired product.

as colorless crystals, m.p. 195 196C Analysis for C H NO Calculated: C,65.10; H, 5.46; N, 10.85

Found: C, 64.98; H, 5.39; N, 1076 IR spectrum (Nujol Mull, cm") 112650,142

NMR spectrum ('1', (CD SO) 7.67 (3H, s, C -CH 4.89 (2H, s, C -CH O) 2.233.03 (6H, m, NH and aromatic H) 2.0 (1H, d, J=2.0, C,-H)

127 (1H, d, J=2.0, C -H) REFERENTIAL EXAMPLE l25-Methoxycarbonyloxymethyl-2-methyl-3pyridinol (No. 87)

To a solution of 1.8 g. of 5-hydroxymethyl-2-methyl 3pyridinolhydrochloride in 10 ml. of pyridine was added 1.0 g. ofmethylchlorocarbonate dropwise under cooling. After standing overnight, thereaction mixture was poured into ice water and extracted with ethylacetate. The extract was washed with water, dried and the solvent wasdistilled off to give 1.0 g. of an oily substance. The oily substancewas purified by column chromatography (silica gel g.) and 0.6 g. of thedesired product as colorless crystal was obtained from the eluate withbenzeneethyl acetate (3:7) and recrystallized from ethyl acetate andn-hexane.

Colorless crystal, mp. 187 188C (dec) Analysis for C H NO Calculated: C,54.82; H, 5.62; N, 7.10

Found: C, 55.02; H, 5.91; N, 7.47 IR spectrum (Nujol Mull, cm") v,2500,v 1740 7.60 (3H, s, c,-CH,)

6.22 (3H, s, coocru) 4.84 (2H, s, C -CH OCOOCH 2.72 (1H, (1, 1:2, 01H)1.95 (1H, d. 1 2, c,-H)

REFERENTIAL EXAMPLE l3 I was adjusted to pH 1 1.5 with 10 percenthydrobromic acid. The mixture was heated at C for 30 minutes, thencooled and neutralized with sodium bicarbonate and extracted with ethylacetate. The extract was dried over anhydrous sodium sulfate andconcentrated into a small volume and the addition of n-hexane gave 0.45g. of the desired product as colorless crystals melting at 187 189C,which showed no depression of melting point on admixture with theauthentic sample and the IR spectrum coincided with that of the standardcompletely.

REFERENTIAL EXAMPLE l4 2-(2-Furoyloxy)-5-(2-furoyloxymethyl)-2-methylpyridine (No. 1 16) To a solution of 0.9 g. ofS-hydroxymethy1-2-methyl- 3-pyridinol hydrochloride in 15 ml. ofpyridine was added 1.3 g. of furoyl chloride and the mixture was stirredat room temperature for 15 hours. Pyridine was distilled off underreduced pressure and the residue was poured into 15 ml. of water,neutralized with sodium bicarbonate and extracted with ethyl acetate.The extract was dried over anhydrous sodium sulfate an oily substanceobtained by removal of the solvent was crystallized from ethanol to give1.5 g. of the desired product.

Colorless crystal, m.p. 1 18 1 19C Analysis for C H NO Calculated: C,62.38; H, 4.00; N, 4.28

Found: C, 62.75; H, 4.21; N, 4.14

IR spectrum (Nujol Mull, cm)

Following the substantially same procedure as described in the abovereferential example 14, those pyridine derivatives as recited below wereprepared: 3-Acetoxy-5-acetoxymethyl-Z-methylpyridine hydrochloride(hydrochloride of No. 2)

Colorless crystal, m.p. 122 125C Analysis for C l-l ClNO Calculated: C,50.80; H,5.39; N, 5.39; Cl, 13.66

Found: C, 56.68; H, 5.52;N, 5.40; Cl, 13.43

IR spectrum (Nujol Mull, cm)

1 1770, 1740 2-Methyl-3-propionyloxy-5-propionyloxymethylpyridine (No.3)

Colorless oil Analysis for C H NO Calculated: C. 62.14; H, 6.82; N, 5.57

Found: C. 62.10; H, 6.80; N, 5.62

IR spectrum (liquid film, cm)

V('=() 1770, 1750 3-Butyryloxy-5-butyryloxymethyl-2-methylpyridine (No.4)

Colorless oil,

Analysis for C H NO Calculated: C, 64.49; H, 7.58; N, 5.01

Found: C, 64.20; H, 7.59; N. 5.11

IR spectrum (liquid film, cm)

w 1764, 1742 3-lsobutyryloxy-5-isobutyryloxymethyl-2 methylpyridinehydrochloride (hydrochloride of No.

Colorless crystal, m.p. 134 136C Analysis for C H ClNQ,

Calculated: C, 57.10; H, 6.97; N, 4.43; Cl, 11.25

Found: C, 57.14; H, 6.94; N, 4.77; Cl, 11.27

1R spectrum (Nujol Mull, cm)

1/ 3-Cyclohexanecarbonyloxy-S-cyclohexanecarbonyloxymethyl-2-methylpyridine drochloride (hydrochlorideof No. 104) Colorless crystal, m.p. 148 151C Analysis for C H ClNOCalculated: C, 63.7; H, 7.58; N, 3.54; Cl, 8.97

Found: C, 64.0; H, 7.67; N, 3.85; Cl, 8.953-Crotonoyloxy-S-crotonoyloxymethyl-2- methylpyridine (No. 101)Colorless oil,

Analysis for C H NO Calculated: C, 65.44; H, 6.22; N, 5.09

Found: C, 65.40; H, 6.16; N, 5.32

1R spectrum (liquid film, cm)

1 1740, 1720 3-Benzoyloxy-5-benzoyloxymethyl-2-methylpyridine (No. 119)Colorless crystal, m.p. 85 86C Analysis for C H NO Calculated: C, 72.61;H, 4.93; N, 4.03

Found: C, 72.63; H, 4.83; N, 4.333(p-Chlorobenzoyloxy)-5-(pchlorobenzoyloxymethyl)-2-methylpyridine (No.120) Colorless crystal, m.p. 157 159C Analysis for C H Cl NO Calculated:C, 60.40; H, 3.61; N, 3.37; C1, 17.09

Found: C, 60.23; H, 3.78; N, 3.36; Cl, 16.84

REFERENTIAL EXAMPLE 15 3-Ethylcarbamoyloxy-S-ethylcarbamoyloxymethyl-Z-methylpyridine (No. 122) To a solution of 0.9 g. of5-hydroxymethyl-2-methyl- .3-pyridinol hydrochloride in 10 ml. ofpyridine was added 0.8 g. of ethyl isocyanate and the mixture wasstirred at 100C for 2 hours. After cooling, the mixture was poured intoice water and extracted with chloroform. The extract was washed withwater, dried over anhydrous sodium sulfate and the solvent was distilledoff to give a crystalline product, which was recrystallized from ethylacetate-n-hexane to give 0.95 g. of the desired product as colorlesscrystals.

Analysis for C H N O Calculated: C, 55.50; H, 6.81; N, 14.94

Found: C, 55.10; H, 6.74; N, 15.20

IR spectrum (Nujol Mull, cm)

P 3330, 14: 1710, 1690 NMR spectrum (7, CDCI CDCI 8.88 (3H, t, .l=7)8.77 (3H, t, 1 7 7.55 (3H, s, C -CH 6.5 7.0 (4H, m) 4.90 (2H, s, C -CH4.90 (1H, broad, NH) 4.50 (1H, broad, NH) 2.52 (1H, d, J=2.0, C -H) 1.67(11-1, d, J=2.0, C -H) REFERENTIAL EXAMPLE 163-Methoxycarbonyloxy-S-methoxycarbonyloxymethyl- Z-methylpyridine (No. l1 1) To a solution of 0.9 g. of 5-hydroxymethyl-2-methyl- 3-pyridinolhydrochloride in 10 ml. of pyridine was added 1.0 g. of methylchlorocarbonate dropwise under cooling. After standing overnight, thereaction mixture was poured into ice water and extracted with ethylacetate.

The extract was washed with water, dried over anhydrous sodium sulfateand the solvent was distilled off. The resulting residue wasrecrystallized from ethyl acetate and n-hexane to give 0.6 g. of thedesired product as colorless crystals. I

m.p. 65C

Analysis for C H NO Calculated: C, 51.76; H, 5.49; N, 5.49

Found: C, 52.08; H,-5.31; N, 5.69

IR spectrum (Nujol Mull, cm)

NMR spectrum (1', CDCl 7.52 (3H, s, C -CH 6.20 (3H, s, COOCH 6.06 (3H,s, COOCH 4.82 (2H, s, C -CH OCOOCl-l 2.42 (1H, d, J=2.0, C -H)REFERENTIAL EXAMPLE l7 3-Acetoxy-S-benzoyloxymethyl-Z-methylpyridine(No. 91

To a solution of 1.1 g. of 3-acetoxy-5-hydroxymethyl- Z-methylpyridinehydrochloride in 10 ml. of pyridine was added 0.8 g. of benzoyl chloridedropwise under cooling.

The mixture was stirred overnight at room temperature, then poured intoice water and extracted with ethyl acetate. The extract was washed withwater, dried and the solvent was distilled off to give an oilysubstance, which was purified by column chromatography (silica gel 30g.) An oily. substance obtained from the eluate with benzene-ethylacetate (8:2) was crystallized from ethyl acetate and n-hexane to give1.35 g. of the desired product as colorless crystals.

m.p. 57C

Analysis for C H NO Calculated: C, 67.36; H, 5.30; N, 4.91

Found: C, 67.36; H, 5.17; N, 4.82

IR spectrum (Nujol Mull, cm)

NMR spectrum ('r, CDClg) l? 7.65 (3H, 5, OCCH 7.55 (3H, za) 4.62 (2H, s,c -cn oco- 2.3 2.6 (4H, m, Aromatic H) 1.85 2.0 (1H, m, Aromatic H) 1.83(1H, d, .l=2.0, C -H) 1.52 (1H, d, J=2.0, C -H) Following thesubstantially same procedure as shown in referential example 17, thosepyridinol derivatives recited below were prepared.3-Acetoxy-5-(p-methoxybenzoyloxymethyl)-2- methylpyridine (No. 93)

Colorless crystal, m.p. 65 66C Analysis for C H NO Calculated: C, 64.75;H, 5.43; N, 4.44

Found: C, 64.71; H, 5.40; N, 4.123-Acetoxy-5-(2-furoyloxymethyl)-2-methylpyridine (No. 94)

Colorless oil R value of thin-layer chromatography: 0.76 (Plate,Dc-Fertig platten Keiselgel available from Merck Co., Ltd., Developingsolvent, ethyl acetate) Analysis for C H NO Calculated: C, 61.09; H,4.76; N, 5.09

Found: C, 60.79; H, 4.52; N, 15.355-Acetoxymethyl-3-benzoyloxy-2-methylpyridine drochloride (hydrochlorideof No. 105) Colorless crystal, m.p. 148 150C Analysis for C H ClNOCalculated: C, 59.75; H, 4.98; N, 4.36; Cl, 11.02

Found: C, 59.76; H, 5.02; N, 4.63; Cl, 10.813-Acetoxy-5-cyclohexanecarbonyloxymethyl-2- methylpyridine (No. 95)

Colorless oil Analysis for C H NO Calculated: C, 65.95; H, 7.27; N, 4.81

Found: C, 65.83; H, 7.30; N, 4.76

IR spectrum (liquid film, cm)

vC=O 1776, 1736 REFERENTIAL EXAMPLE l83-Benzyloxy-S-hydroxymethyl-2-methylpyridine (No. 23)

To a solution of 1.7 g. of 5-hydroxymethyl-2- methyl3-pyridinolhydrochloride in m1. of dimethylformamide was added a solution of 0.9 g.of 50% sodium hydride in 6 ml. of dimethylformamide. The mixture wasstirred at roomtemperature for 3 hours and to the solution was added1.25 g. of benzyl chloride and additional stirring was continuedovernight at room temperature.

The reaction mixture was diluted with water and extracted with ethylacetate.

The extract was washed with water, dried and the solvent was distilledoff to give an oily substance. Thereaf ter,.the oil was subjected tosilica gel dry column chromatography to give 1.1 g. of crystallineproduct, which was recrystallized from benzene and cyclohexane to givethe desired product as colorless crystals.

m.p. 77 79C Analysis for C H NO Calculated: C, 73.34; H, 6.59; N, 6.11

Found: C, 73.64; H, 6.75; N, 6.61

IR spectrum (Nujol Mull, cm)

NMR spectrum (1', CDCl 7.57 (3H, s, C -CH 5.39 (2H, s, C -CH OH) 4.99(2H, s, C3-OCH2 2.77 (1H, d, J=1.5, c.-H) 2.10 (1H, d. J=1.5, C -H)REFERENTlAL EXAMPLE 19 5-Methoxymethyl-2-methyl-3-pyridinol (No. 20)

2 g. of 5-bromomethyl-2-methyl-3-pyridinol was refluxed in 50 ml. ofanhydrous methanol for 20 hours. The solvent was distilled off and theresidue was poured on water, shaken with ethyl acetate and the ethylacetate layer was discarded. The aqueous layer was neutralized withsodium bicarbonate and extracted with ethyl acetate.

The extract was washed with water, dried and the solvent was distilledoff.

The resulting oil which crystallized gradually was recrystallized fromethanol-petrolium ether to give 0.82 g. of the desired product ascolorless crystals.

m.p. 134 -135C Analysis for C,,H,,NO

Calculated: C, 62.72; H, 7.24; N, 9.14

Found: C, 62.58; H, 7.46; N, 8.95

IR spectrum (Nujol Mull, cm") NMR spectrum (1", (CD SO) 7.64 (3H, s, C-CH 6.73 (3H, s, C -CH OCH 5.65 (2H, s, C -CH OCH;)

2.9 (1H, d, J=2.0, C,-H)

Following the substantially same procedure as shown in referentialexample 19, the pyridinol derivative recited below was obtained:5-Benzyloxymethyl-2-methyl-3-pyridinol (No. 21)

Colorless crystal, m.p. 135 137C Analysis for C H NO Calculated: C,73.34; H, 6.59; N, 6.11

Found: C, 73.22; H, 6.61; N, 6.33

The compounds of the formula (1) or the salts thereof are convenientlyfed to poultry as a component of the feed or drinking water, but theymay also be administered orally dispersed or admixed with othercarriers.

According to one aspect of this invention, novel compositions areprovided in which a pyridinol derivative or the salt thereof (1) ispresent as an active ingredient. Such compositions comprise thepyridinol derivative intimately dispersed in or admixed with an inertcarrier. The term inert carrier as used herein means one that issubstantially non-reactive with the active ingredient, orally ingestableand tolerated by the poultry.

The amount of pyridinol derivative required for control of coccidiosisin poultry will vary somewhat with the specific compound employed, thespecies of animals, the method or the object of application or with thesymptons. Generally, the pyridinol derivatives (1) are effective inpreventing the disease without undesirable side effect and toxic effectwhen administered at a level of more than about 0.005 percent by weightof cent to about 0.2percent by weight of the fe'ed'mayabe advantageouslyadministered for treatment of coccidio sis. When these compounds are tobe employed for therapeutic purpose, it is desirable to employ thelowestlevels that exhibit anticoccidial activities, in order to eliminate anyrisk of side effects that may appear on prolonged feeding. i

In preparing solid compositions, an uniform dispersion of the activeingredient throughout the carrier can be readily accomplished by theconventional methods of grinding, stirring or milling.

Many of these pyridinol: derivatives or the salts thereof areadvantageously administered to poultry by way of the drinking water ofthe birds. This method of treatment may often be employed in thetherapeutic use, since poultry with coccidiosis are apt to consume lesssolid feed than normal birds. The water-soluble quaternary salts may beadded directly to the drinking water.

According to another aspect of this invention, novel compositions areprovided in which active ingredient is present in relatively largeamounts and which are suitable for addition to the poultry feed directlyor after intermediate dilution step. Such compositions which are apreferred feature of this invention are the so-called feed supplementsor premix. Representative examples of the carriers to be employed inthis invention are solid oral carriers such as distillers dried grains,corn starch, potato starch, fermentation residues, ground oyster shells,Attapulgus clay, rice bran, wheat bran, wheat middling, molassessolubles, corn meal, edible vegetable substances, soybean cake, soybeanmeal, antibiotic mycelis, crushed lime stone and the like. Thequaternary salts are intimately dispersed oradmixed throughout the solidinert carrier as described hereinabove. Formulations containing fromabout percent to about 30 percent by weight, and preferably-from about25 percent by weight of the active ingredient are particularly suitablefor this purpose. It is preferable in the industry to use about 1 3 kg.of such a supplement per ton of feed.

Typical feed supplements containing pyridinol derivatives dispersed inan inert carrier include, for example, the following:

quaternary salt parts by weight S-hydroxymcthyl-Z-methyl- According toanother aspect of this invention, the present composition may preferablyinclude other known anticoccidial agents to broaden its anticoccidialspectrum and, sometimes, expect a synergistic effect.

Suitable examples of such anticoccidial agents include, for example,sulfa drugs, e.g., Sulfachloropyrazine, Sulfadimethoxine,Sulfaquinoxaline; thiamine derivatives, e.g., Beclotiamine, Amprolium,Dimethialium; quinoline derivatives, e.g., Buquinolate, Decoquinate,Methyl Benzoquate; folic acid antagonistic substances, e.g.,pyrimethamin, Diaveridine; antibiotics, e.g., Monensin; Zolene(3,5dinitr'o-o-toluamide), Clopidol(3,5-dichloro-2,6-dimethyl4-pyridinol), Robenzidine; and the like.

The formulation of the compounds and the coccidiostatic activity of thecompounds are more fully illustrated by the non-limiting examples asfollows.

In these examples, all the parts are given by weight unless otherwiseindicated.

EXAMPLE 1.

Fifteen parts of 5-hydroxymethyl-2methyl-3 pyridinol are uniformly mixedwith parts of wheat bran.

The resulting feed supplement contains 15% active ingredient. Uniformmixing of one part of the supplement with 1,000 parts of the poultryfeed gives a feed composition containing 0.015% active ingredient.

EXAMPLE 2.

Five parts of S-hydroxymethyl-2-methyl-3-pyridinol and 5 parts ofSulfachloropyradine are uniformly mixed with parts of rice bran.

The resulting feed supplement contains 10% active ingredients in total.One parts of the supplement is uniformly mixed with 10,000 parts of thepoultry feed to give a feed containing 0.01% active ingredient in total.

EXAMPLE 3.

The coccidiostatic activity of the pyridinol derivatives (I) or thesalts thereof of this invention is determined by the following method:

Test Procedures 1. Chicks: Fourteen-day-old White Leghorn males (afterhatched, fed a diet containing no anticoccidial agent and isolated asfar as possible from the risk of extraneous coccidial infections) wereused.

Each group consisted of 10 chicks so as to avoid the difference of meanweight (significance level, 5 percent).

(2) Infections: Each chick was inoculated orally into the crop with100,000 sporulated oocysts of Eimeria acervulina. 3. Concentration oftested compouds: Each tested compound was mixed to the commerciallyavailable mixed feed at the concentration of 200 ppm.

After inoculation with oocysts, the chicks are fed a diet containingtested compounds for 6 days.

Control groups of infected or non-infected chicks are fed a similar dietwhich is free from coccidiostat.

They are weighed from the beginning of the test to the end, constantly.Daily oocyst outputs are determined as oocysts per gram feces during aperiod from day 4 to 6. The daily samples from each treatment are pooledand recorded as a percentage to that of the infected-unmedicatedcontrol.

At the end of this time, that is, six days after infection all chicksare sacrificed and the degree of the lesion of small intestines areindicated as a 0 to 4 visual scale 5 and determined by the method ofJohnson and Reid described in Experimental Parasitology vol. 28.

4. Explanation of findings set forth in Table 1 and 2:

Relative rate of weight gain (71) Rate of oocyst production (71 Oocystoutputs of each Oocyst outputs of infected unmedicated group x Theaccumulated oocyst outputs per gram feces, during a period from day 4 to6 is defined as oocyst number.

Mean lesion score of intestine Total intestinal lesion of scores 8Number of chicks The results are shown in Table 1.

Table 1 Rate of Relative Mean lesion oocyst rate of score of CompoundNo. production weight intestine (71) gain (71) 1 0 95.5 0 l(hydrochloride) 1.1 91.0 1.5 2 0 95.0 0 3 0 94.3 0 4 0 94.1 0 9 5.0 90.50.7 10 2.8 92.4 0.5 17 5.1 90.7 0.6 20 3.9 83.9 1.6 21 1.5 93.5 2.0 25(hydrochloride) 0.1 100.0 0.3 29 (hydrochloride) 1.1 89.3 1.6 30 1.090.0 1.7 36 (hydrochloride) 0.3 102.0 0.8 38 2.2 89.4 1.2 39 0.6 103.00.6 40 0.9 97.8 0.3 42 0.3 97.8 1.0 49 2.4 70.6 1.2 50 1.8 90.4 1.0 520.8 93.9 0.4 56 2.0 81.0 1.9 57 0 97.8 0 58 0 94.4 0 60 0 103.0 0 62 0101.5 0 66 1.4 94.5 1.8 67 0.5 97.9 0.6 68 (hydrochloride) 0.4 90.7 1.070 0.9 91.3 0.8 78 1.4 88.5 1.4 79 1.4 84.6 0.6 86 0 96.0 0 87 4.0 90.00.9 91 2.4 84.7 0.8 93 2.7 70.4 1.2 101 1.4 94.7 1.0 104 0.9 96.0 1.0105 1.5 85.8 0.9 1 l l 4.5 90.0 0.9 1 16 0.5 93.5 1.0 120 2.2 72.5 1.6infectedunmedicatcd control 100 60.1 4.0 uninlcctcd-unmedicated control100 It will be evident from the above results that the pyridinolderivatives of the abovementioned formula (I) or the salts thereofpossess an extremely high degree of activity which cause coccidiosis,accompanying with good weight gain of the poultry without anyunfavorable side effects.

lt has also turned out that the coccidiostatic effect of i the presentcomposition was the highest at the first chizogony followed by thegametogony in various developmental stage of coccidia.

EXAMPLE 4 i The coccidiostatic activity of the present compounds incombination with known anticoccidial agents was tested. The testprocedure, chicks and coccidia used were substantially the same as shownin Example 3.

The results are shown in Table 2.

Table 2 Cone. of Rate of Relative Mean active oocyst rate of lesionCompound ingredient proweight score of tested in feed duction gain (/z)intestine 2-methyl-5-hydroxy-3-pyr- 0.005 idinol 3.0 95.0 0.8Beelotiaminc 0.01 hydrochloride 2-methyl-5-hydroxy-3-pyri- 0.005 dinol0.5 97.0 0.1 Sulfachloro- 0.01 pyrazine lmethyl-S-hydroxy-3pyr.i- 0.00513.0 82.3 2.0 dinol Beclotiamine 0.01 31.0 78.5 2.4 hydrochlorideSulfachloro- 0.005 21.5 82.0 2.1 pyrazine lnfectedunmedii 59.3 4.0 catedcontrol Uninfected-unmedicated 100 control,

/ CH OR CH3 \N wherein R and R may be the sameor different and eachrepresents a hydrogen atom; a lower alkyl group;

benzyl; a halogen-substituted benzyl group; an unsubstituted straight orbranched chain alkanoyl or alkenoyl group having a total of from 2 to 18carbon atoms or substituted with a phenoxy group or a cycloalkanoylgroup having a total of from 6 to 8 carbon atoms; an unsubstitutedbenzoyl or naphthoyl group or substituted with from 1 to 2 lower alkyl,alkoxy, halogen, nitro, cyano. carboxy or aeetylamino groups; analkoxycarbonyl group; a benzyloxycarbonyl group; a phenoxycarbonylgroup; an unsubstituted carbamoyl group or substituted on the nitrogenatom thereof with a lower alkyl group of 1 to 2 carbon atoms, acycloalkyl group of to 7 carbon atoms or chlorophenyl group; an unsubstituted thiocarbamoyl group or substituted on the nitrogen atomthereof with a lower alkyl group of l to 2 carbon atoms, a cycloalkylgroup of 5 to 7 carbon atoms or chlorphenyl group; or a salt thereof.

2. The anticoccidial composition according to claim 1 wherein R ishydrogen atom and R, is an alkanoyl group of 2 to 8 carbon atoms, analkenoyl group of 2 to 8 carbon atoms, a cycloalkanoyl group of 6 to 8carbon atoms, a benzoyl group unsubstituted or substituted with a methylor a methoxy group.

3. The anticoccidial composition according to claim 1 wherein R ishydrogen atom and R is an alkanoyl group of 2 to 8 carbon atoms, analkenoyl group of 2 to 8 carbon atoms, or a cycloalkanoyl group of 6 to8 carbon atoms,

4. The anticoccidial composition according to claim 1 wherein R and Rmay be the same or different and each represents an alkanoyl group of 2to 8 carbon atoms or an alkenoyl group of 2 to 8 carbon atoms.

5. The anticoccidial composition according to claim 1 wherein R ishydrogen atom and R is an alkanoyl group of 2 to 8 carbon atoms.

6. The anticoccidial composition according to claim 1 wherein R ishydrogen atom and R is an alkanoyl group of 2 to 8 carbon atoms.

7. The anticoccidial composition according to claim 1 wherein activecompound is 5-hydroxymethyl-2- methyl3-pyridinol.

8. The poultry feed of claim 1, wherein said salt is an acid adduct saltof said compound and an acid selected from the group consisting ofhydrochloric, sulfuric, nitric, phosphonic, acetic, propionic, lactic,oxalic, succinic, maleic, tartaric, citric, benzoic, phthalic,terephthalic and naphthalene sulfonic acid.

9. The poultry feed of claim 1, wherein said compound is5acetoxy-2-methyl-3-pyridinol.

10. The poultry feed of claim 1, wherein said compound is2-methyl-5-propionyloxymethyl-3-pyridinol.

11. The poultry feed of claim 1, wherein said compound is2-methyl-5-valeroyloxymethyl-3-pyridinol.

12. The poultry feed of claim 1, wherein said compound is2-methyl-5-octanoyloxymethyb3-pyridinol.

13. A method of controlling poultry coccidiosis which comprises orallyadministering to poultry susccptible to coccidiosis an anticoccidialamount of a compound of the formula 1 CHZORZ wherein R and R may be thesame or different and each represents a hydrogen atom; a lower alkylgroup; benzyl; a halogen-substituted benzyl group; an unsubstitutedstraight or branched chain alkanoyl or alkenoyl group having a total offrom 2 to 18 carbon atoms or substituted with a phenoxy group or acycloalkanoyl group having a total of from 6 to 8 carbon atoms; anunsubstituted benzoyl or naphthoyl group or substituted with from 1 to 2lower alkyl, alkoxy, halogen, nitro, cyano, carboxy or acetylaminogroups; an alkoxycarbonyl group; a benzyloxycarbonyl group; aphenoxycarbonyl group; an unsubstituted carbamoyl group or substitutedon the nitrogen atom thereof with a lower alkyl group of l to 2 carbonatoms, a cycloalkyl group of 5 to 7 carbon atoms or chlorophenyl group;an unsubstituted thiocarbamoyl group or substituted on the nitrogen atomthereof with a lower alkyl group of l to 2 carbon atoms, a cycloalkylgroup of 5 to 7 carbon atoms or chlorophenyl group; or a salt thereof.

14. The method of controlling poultry coccidiosis according to claim 13wherein R is a hydrogen atom and R is an alkanoyl group of 2 to 8 carbonatoms, an alkenoyl group of 2 to 8 carbon atoms, a cycloalkanoyl groupof 6 to 8 carbon atoms, or a benzoyl group unsubstituted or substitutedwith a methyl or a methoxy group.

15. The method of controlling poultry coccidiosis according to claim 13wherein R is a hydrogen atom and R is an alkanoyl group of 2 to 8 carbonatoms, an alkenoyl group of 2 to 8 carbon atoms, or a cycloalkanoylgroup of 6 to 8 carbon atoms.

16. The method of controlling poultry coccidiosis according to claim 13wherein R and R may be the same or different and each represents analkanoyl group of 2 to 8 carbon atoms or an alkenoyl group of 2 to 8carbon atoms.

17. The method of controlling poultry coccidiosis according to claim 13wherein R is hydrogen atom and R is an alkanoyl group of 2 to 8 carbonatoms.

18. The method of controlling poultry coccidiosis according to claim 13wherein R is a hydrogen atom and R is an alkanoyl group of 2 to 8 carbonatoms.

19. The method of controlling poultry coccidiosis according to claim 13wherein active compound is S-hydroxymethyl-Z- methyl-3-pyridinol.

20. The method of claim 13, wherein said salt is an acid adduct salt ofsaid compound and an acid selected from the group consisting ofhydrochloric, sulfuric, nitric, phosphonic, acetic, propionic, lactic,oxalic, succinic, maleic, tartaric, citric, benzoic, phthalic,terephthalic and naphthalene sulfonic acid.

21. The method of claim 13, wherein said compound is a5-acetoxy-2-methyl-3-pyridinol.

22. The method of claim 13, wherein said compound is2-methyl-5-propionyloxymethyl-3-pyridinol.

23. The method of claim 13, wherein said compound is2-methyl-5-valeroyloxymethyl-3-pyridinol.

24. The method of claim 13, wherein said compound isZ-methyl-5-octanoyloxymethyl-3-pyridinol.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION 556PATENT NO 3,897, Page 1 of DATED July 29, 1975 |N\/4ENTOR(S) YASUHIROMORISAWA et al It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Column 3, line 6: replace "hydrgoen" with hydrogen Column 3, line 19:replace "preferably" with preferable Column 4, No. 67: replace"-2lmethyl-" with 2-methyl- Column 6, lines 27-28: insert a commabetween "pyridinol" and "2-methyl".

Column 7, line 10 and Column 9, line 21: replace "5hydroxymethyl" with5-hydroxymethyl Column 10, line 44:

Column 12, line 56: replace 3pyridinol" with 3-pyridinol Column 13, line31; Column 14, line 8;

and Column 14, line 26:

replace "methyl3" with methyl-3 Column 15, line 21: replace "4,96" with4.96

B-pyridinol Column 17, line 40 and line 41: replace "C H" with C -E andreplace "C H" with C replace "Accordin" with According PATENT NO.

DATED iN\/ ENTOR(S) Column Column Column Column Column Column ColumnColumn Column [SEAL] UNITED STATES PATENT AND'TRADEMARK OFFICECERTIFICATE OF CORRECTION it is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Column 17, line 48: replace "Zmethylpyridine" with YASUHIRO MORISAWA etal Page 2 of 2 2-methylpyridine line 41: delete "v NHOH 2650" andreplace with line 47: replace "methyl3" with methyl-3- line 8: replace"3,5dinitro" with 3,5-dinitro line 9: replace "dimethyl4" withdimethyl-4- line 5: replace "chlorphenyl" with chlorophenyl Claim 7:replace "active" with Said Claim 19: replace "active" with saidsixteenth Day of March 1976 Arrest:

RUTH c. MASON A nesting Officer C. MARSHALL DANN Commissioner of Parentsand Trademarks

1. A POULTRY FEED HAVING DISPERSED THEREIN FOR CONTROLL OF POULTRYCOCCIDIOSIS FROM ABOUT 0.005% TO ABOUT 0.05% BY WEIGHT OF A COMPOUND OFTHE FORMULA
 2. The anticoccidial composition according to claim 1wherein R2 is hydrogen atom and R1 is an alkanoyl group of 2 to 8 carbonatoms, an alkenoyl group of 2 to 8 carbon atoms, a cycloalkanoyl groupof 6 to 8 carbon atoms, a benzoyl group unsubstituted or substitutedwith a methyl or a methoxy group.
 3. The anticoccidial compositionaccording to claim 1 wherein R1 is hydrogen atom and R2 is an alkanoylgroup of 2 to 8 carbon atoms, an alkenoyl group of 2 to 8 carbon atoms,or a cycloalkanoyl group of 6 to 8 carbon atoms.
 4. The anticoccidialcomposition according to claim 1 wherein R1 and R2 may be the same ordifferent and each represents an alkanoyl group of 2 to 8 carbon atomsor an alkenoyl group of 2 to 8 carbon atoms.
 5. The anticoccidialcomposition according to claim 1 wherein R2 is hydrogen atom and R1 isan alkanoyl group of 2 to 8 carbon atoms.
 6. The anticoccidialcomposition according to claim 1 wherein R1 is hydrogen atom and R2 isan alkanoyl group of 2 to 8 carbon atoms.
 7. The anticoccidialcomposition according to claim 1 wherein active compound is5-hydroxymethyl-2-methyl3-pyridinol.
 8. The poultry feed of claim 1,wherein said salt is an acid adduct salt of said compound and an acidselected from the group consisting of hydrochloric, sulfuric, nitric,phosphonic, acetic, propionic, lactic, oxalic, succinic, maleic,tartaric, citric, benzoic, phthalic, terephthalic and naphthalenesulfonic acid.
 9. The poultry feed of claim 1, wherein said compound is5-acetoxy-2-methyl-3-pyridinol.
 10. The poultry feed of claim 1, whereinsaid compound is 2-methyl-5-propionyloxymethyl-3-pyridinol.
 11. Thepoultry feed of claim 1, wherein said compound is2-methyl-5-valeroyloxymethyl-3-pyridinol.
 12. The poultry feed of claim1, wherein said compound is 2-methyl-5-octanoyloxymethyl-3-pyridinol.13. A method of controlling poultry coccidiosis which comprises orallyadministering to poultry susceptible to coccidiosis an anticoccidialamount of a compound of the formula
 14. The method of controllingpoultry coccidiosis according to claim 13 wherein R2 is a hydrogen atomand R1 is an alkanoyl group of 2 to 8 carbon atoms, an alkenoyl group of2 to 8 carbon atoms, a cycloalkanoyl group of 6 to 8 carbon atoms, or abenzoyl group unsubstituted or substituted with a methyl or a methoxygroup.
 15. The method of controlling poultry coccidiosis according toclaim 13 wherein R1 is a hydrogen atom and R2 is an alkanoyl group of 2to 8 carbon atoms, an alkenoyl group of 2 to 8 carbon atoms, or acycloalkanoyl group of 6 to 8 carbon aToms.
 16. The method ofcontrolling poultry coccidiosis according to claim 13 wherein R1 and R2may be the same or different and each represents an alkanoyl group of 2to 8 carbon atoms or an alkenoyl group of 2 to 8 carbon atoms.
 17. Themethod of controlling poultry coccidiosis according to claim 13 whereinR2 is hydrogen atom and R1 is an alkanoyl group of 2 to 8 carbon atoms.18. The method of controlling poultry coccidiosis according to claim 13wherein R1 is a hydrogen atom and R2 is an alkanoyl group of 2 to 8carbon atoms.
 19. The method of controlling poultry coccidiosisaccording to claim 13 wherein active compound is5-hydroxymethyl-2-methyl-3pyridinol.
 20. The method of claim 13, whereinsaid salt is an acid adduct salt of said compound and an acid selectedfrom the group consisting of hydrochloric, sulfuric, nitric, phosphonic,acetic, propionic, lactic, oxalic, succinic, maleic, tartaric, citric,benzoic, phthalic, terephthalic and naphthalene sulfonic acid.
 21. Themethod of claim 13, wherein said compound is a5-acetoxy-2-methyl-3-pyridinol.
 22. The method of claim 13, wherein saidcompound is 2-methyl-5-propionyloxymethyl-3-pyridinol.
 23. The method ofclaim 13, wherein said compound is2-methyl-5-valeroyloxymethyl-3-pyridinol.
 24. The method of claim 13,wherein said compound is 2-methyl-5-octanoyloxymethyl-3-pyridinol.